An oral TNFα inhibitor for inflammatory bowel disease

口服 TNFα 抑制剂治疗炎症性肠病

• 批准号: 10603230
• 负责人: GRANT H RISDON
• 金额: $ 30万
• 依托单位: D BIOTHERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603230
• 关键词: Affinity; Antibodies; Binding; Biological Products; Blood Circulation; Chronic Disease; Clinical; Colitis; Colon; Crohn' s disease; Cultured Cells; Cyclic Amino Acids; Cyclic Peptides; Digestion; Disease; Disease model; Dose; Enzymes; Genes; Goals; Hospitalization; Human; Humira; Image; Immunosuppression; In Vitro; Infection; Inflammatory; Inflammatory Bowel Diseases; Intellectual Property; Intraperitoneal Injections; Mediating; Membrane; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Mus; Oral; Oral Administration; Outcome; Patients; Penetration; Peptides; Permeability; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Prevalence; Proteolysis; Resistance; Risk; Site; Small Business Innovation Research Grant; Symptoms; TNF gene; Testing; Therapeutic; TimeLine; Tissues; Toxic effect; Transgenic Mice; Tumor Necrosis Factor Receptor; Ulcerative Colitis; Work; absorption; adalimumab; antigen processing; dextran sulfate sodium induced colitis; disability; experience; ileum; inhibitor; innovation; jejunum; murine colitis; peptide L; risk benefit ratio; small molecule; systemic inflammatory response; systemic toxicity; tumor necrosis factor-alpha inhibitor

Project Summary Inflammatory bowel disease is a group of disorders (Crohn’s disease and Ulcerative Colitis) that are associated with substantial morbidity and disability for millions of people worldwide. Although multiple biologic agents and small molecules are approved for the treatment, anti-TNF monoclonal antibodies remain first line therapy. Yet, clinical benefit from these agents is lost in ~30% of patients due to neutralizing anti-drug antibodies (ADAs). Systemic administration results in immunosuppression with heightened risk for serious infections. Efforts to develop gut-restricted oral anti-TNF antibodies (for convenience and to avoid systemic toxicity) have shown treatment benefit but have not been clinically feasible due to the high doses required to overcome proteolytic gut enzyme digestion. DBT178 is a trimerized 14 D-amino acid cyclic peptide that binds with exceptional affinity to the TNF trimer. It blocks both soluble and membrane-bound TNF activity and is 400-fold more potent than the leading TNF mAb, adalimumab (Humira®), in vitro. D-peptides are chiral mirror images of natural L-peptides; thus, they are essentially inert to enzymatic proteolysis and are stable over a broad pH range. Thus, orally administered DBT178 should transit intact to sites of IBD (jejunum, ileum and colon), permitting clinically effective dosing. In addition, DBT178 has ~5% the mass of therapeutic anti-TNF mAbs and should have a greater penetration from gut luminal mucosa to submucosal tissues. Oral DBT178 is expected to minimize absorption from gut to portal and systemic circulation (thereby limiting potential systemic toxicity), and its resistance to proteolytic antigen processing will reduce the potential for developing neutralizing anti-DBT178 antibodies. The goal of this Phase I SBIR is to demonstrate DBT178 efficacy following oral delivery in two mouse models of colitis. However, since this inhibitor binds human TNF, but not mouse TNF it will not be effective in conventional IBD models. Accordingly, Aim 1 optimizes DBT178 for oral delivery and tests its inhibition of GI toxicity and systemic inflammation following a single IP injection of high dose hTNF. Aim 2 tests oral DBT178 delivery in a specialized model of DSS-induced acute colitis using B-hTNFA mice, where the human TNFα gene is expressed under normal physiological control following its insertion into the deleted mouse TNF locus. This work plan has a 1-year timeline.

项目概要 炎症性肠病是一组与以下相关的疾病（克罗恩病和溃疡性结肠炎） 尽管有多种生物制剂和药物，但导致全世界数百万人发病和残疾。 小分子被批准用于治疗，但抗 TNFα 单克隆抗体仍然是一线治疗。 由于中和抗药物抗体 (ADA)，约 30% 的患者失去了这些药物的临床益处。 全身给药会导致免疫抑制，并伴有严重感染的哮喘风险。 开发肠道限制性口服抗 TNFα 抗体（为了方便并避免全身毒性）已表明 治疗有益处，但由于克服肠道蛋白水解需要高剂量，因此在临床上不可行 DBT178 是一种三聚化的 14 个 D-氨基酸环肽，以优异的亲和力结合。 TNFα 三聚体可阻断可溶性和膜结合的 TNFα 活性，其效力比 TNFα 三聚体强 400 倍。 领先的 TNFα 单克隆抗体阿达木单抗 (Humira®) 在体外，D 肽是天然 L 肽的手性镜像； 因此，它们对酶促蛋白水解基本上是惰性的，并且在较宽的 pH 范围内稳定。 施用的 DBT178 应完整转运至 IBD 部位（空肠、回肠和结肠），从而实现临床有效 此外，DBT178 的质量约为治疗性抗 TNFα 单克隆抗体的 5%，并且应该具有更大的剂量。 口服 DBT178 有望从肠腔粘膜渗透到粘膜下组织，从而最大限度地减少吸收。 从肠道到门静脉和全身循环（从而限制潜在的全身毒性），及其抵抗力 蛋白水解抗原加工将降低产生中和性抗 DBT178 抗体的可能性。 该 I 期 SBIR 的目标是证明 DBT178 在两种小鼠模型中口服给药后的功效 然而，由于该抑制剂结合人类 TNFα，但不结合小鼠 TNFα，因此对结肠炎无效。 因此，Aim 1 优化了 DBT178 的口服给药并测试其对胃肠道的抑制作用。 单次腹腔注射高剂量 hTNFα 后的毒性和全身炎症 Aim 2 测试口服 DBT178。 使用 B-hTNFA 小鼠在 DSS 诱导的急性结肠炎专门模型中进行递送，其中人类 TNFα 基因 在插入删除的小鼠 TNFα 基因座后，在正常生理控制下表达。 工作计划为期一年。